We earmarked fifteen investigators from West Africa for interviews. However, only four of the five respondents at the EDCTP forum agreed. Of the remaining ten absentees, two agreed to phone interviews. We also interviewed two experienced investigators from Central Africa who were keen and approached the researcher in Lisbon. Interviewed participants had between 6 and 25 years of clinical research experience with a median of 12 years. Three themes emerged from the data analysis. These were; (1) “Experience of sub-Sahara Africa investigators with pregnant women in clinical trials involving investigational agents,” (2) “Barriers to the inclusion of pregnant women in LASV vaccine clinical trials,” and (2) “The enablers of including pregnant women in LASV vaccine clinical trials.”
Experience of sub-Sahara Africa investigators with pregnant women in clinical trials involving investigational agents
The responses revealed that three of the study participants have engaged in clinical trials that involved pregnant women, and most of the experiences with pregnant women were in clinical trials of malaria treatment options in pregnancy.
“I have been involved in a trial of malaria treatment in pregnancy, which occurred in several African countries, and I was declared the investigator for Gabon. So, I had to enroll in that trial about a thousand and two hundred women, pregnant women…and administered some drugs that were for the prevention of malaria during pregnancy and follow them up until delivery and follow the children until their first anniversary" (Participant #9, Investigator, Gabon)
“Yeah, we conducted several studies on pregnant women…there is a one study ongoing now where we are assessing the prevention of neonatal sepsis in pregnant women, where we recruit pregnant women when they come for delivery, and we give them a treatment to prevent the infection of the baby. And, we also conducted a few years ago the biggest clinical trial in malaria treatment in pregnant women, where we tested four drugs in pregnant women and recruited about 850 pregnant women in Nanoro for clinical trials. Before that, we also conducted a PK study in pregnant ... (Participant #2, Clinical Investigator, Burkina Faso)
“Err, clinical trials in pregnant women? only once” (Participant #1, Investigator, Senegal)
The investigators are mostly willing to include pregnant women in LF vaccine clinical trials.
"…for me, if it's important when you want to test a vaccine against an epidemic disease, to include everybody because when the epidemic comes, it will not make a difference between the study groups¬". (Participant #5, Investigator, Ghana)
“Clinical vaccine trial in pregnant women can be done in a carefully controlled and regulated environment, maybe with a higher level of safety monitoring and evaluation than other groups, I think this is possible, and I believe it has been done in some drugs, and this can be extended to vaccine trials too (Participant #6, Investigator, Mali)
“…as far as the vaccine is tested in phase 1 and phase 2 trials and we have robust data to convince the ethics committee and the regulatory authorities that we are not exposing the pregnant women at a higher risk by including them in the study,..…as far as we have enough data to convince them, I think there will not be any problem to include pregnant women in the study” (Participant #3, Investigator, Sierra Leone)
“Looking at it critically, their continued exclusion cannot be scientifically justified even ethically; it is not acceptable because you are excluding a population that is underserved in clinical trials” (Participant #8, Investigator, Congo)
“Although, they are a vulnerable group, with a lot of specific physiologic needs that are different from the nonpregnant populations. It is still paramount that we study them to be able to collect adequate evidence that will be useful when these vaccines are available to the whole population” (Participant #4, Investigator, Nigeria)
However, two of the investigators expressed their reluctance to include pregnant women in a future LF vaccine clinical trial due to a desire to ‘protect them’ and the risk of reputational damage if maternal deaths or teratogenicity occur.
“yes, it is risky in pregnant women because they are usually easily immunocompromised. And because of that, we don’t want to expose them, and again the possibility of teratogenicity for either candidate vaccine or drugs that you have not proven their safety margin and efficacy……. I won’t be keen to conduct such a study” (Participant #7, Investigator, Burkina Faso)
" or the ethics committee may look at this scientist (proposing a study of vaccine efficacy in pregnant women) as chasing personal gain as a scientist by willing to put pregnant women at risk so to speak……. So, nobody wants to have a bad name…" (Participant #5 investigator Ghana)
The responses indicated that pregnant women seemed to have a keen interest in participating in these clinical trials. Most of the investigators believed that everyone, including pregnant women, should be included in clinical trials.
"Even, pregnant women are keener to participate in the study because they think of the baby that the investigator will take care of them better than the normal care provided by the government" and "…for me if it's important when you want to test a vaccine against an epidemic disease, to include everybody because when the epidemic comes, it will not make a difference between the study groups¬". (Participant #5, Investigator, Ghana)
“I told you at the beginning that I am involved in coordinating an Ebola vaccine trial in Sierra Leone, and we included in our age groups… one of the exclusion criteria was that they should not be pregnant at the time of training, so we conduct pregnancy test for them… You need to see the level of emotional disturbance that most of these prospective participants express when they find out that they are excluded on the basis of being pregnant” (Participant #3, Investigator, Sierra Leone).
Some of the participants expressed the view that when excluded from clinical trials, pregnant women show some level of emotional disturbance.
"…for me, if it's important when you want to test a vaccine against an epidemic disease, to include everybody because when the epidemic comes, it will not make a difference between the study groups¬". (Participant #5, Investigator, Ghana).
Barriers to the inclusion of pregnant women in LASV vaccine clinical trials
Participants generally explained that for clinical trials involving investigational new drugs (INDs), the usual recruitment criteria are that female subjects are not pregnant and consent to a pregnancy preventive measure during the clinical trial duration.
“…so that’s why one of the inclusion criteria in many of the vaccine trials which I have been involved is that the woman must undergo a pregnancy test before been enrolled, and when they are enrolled, there will be a period of mandatory contraception, i.e., they will be on any form of contraception that is acceptable to the woman to ensure that the woman does not conceive during the period of active participation in the vaccine trial.” (Participant #3, Investigator, Sierra Leone).
Other barriers to pregnant women participating in clinical trials were identified as
(a) inadequate safety information.
So this study will be very crucial because first, you need to prove the non-teratogenicity of this vaccine in the animal model and also during this childbearing age women, follow them up until they get pregnant to see at the earlier stage of the pregnancy to see if when they get pregnant, this vaccine is still effective. But during pregnancy, it will be a bit difficult if there is no proof of non-teratogenicity of the drug.” (Participant #1, Investigator, Senegal).
(b) Ethical concerns- especially anticipated difficulties in obtaining ethical approval and the competence of ethics committee members in developing countries in reviewing such protocols.
“…but the problem will be the ethics committee and the regulatory authorities, to convince them that we are not exposing pregnant women at a higher risk by enrolling them…No, I think this will also depend on the study design because if you design a study with where you want to recruit a huge number of pregnant women, of course, they will say no; but, if you go gradually to say okay, we will start with first, for instance, five or ten pregnant women…” (Participant #3, Investigator, Sierra Leone).
“Ethical approval might be very challenging, but it is not impossible; it is doable.… you should have all the explanation on hand to give to the ethical committee because your main challenge would be the ethical committee and the quality of the ethical committee members…” (Participant #6, Investigator, Mali).
“Of course, you will need to convince the ethics committees. Usually ethics committee, they’re not very prone to accept clinical trials on venerable populations” (Participant #1, Investigator, Senegal).
(c) the reluctance of trial sponsors to include pregnant women in trials
“… sometimes it’s not the investigator who doesn’t want to do it in most cases but the companies. If the sponsors are not ready to face the extra scrutiny necessary to gain ethics approval or liability, then there is nothing the local investigator can do” (Participant #7, Investigator, Burkina Faso).
(d) appropriate community engagement strategy.
“The community’s attitude will depend on the sensitization process; where you tell them clearly that if an outbreak comes today in the village, it will not decide if you are pregnant or you are not pregnant, so everybody could be afflicted; hence, it will be good to have an idea how this vaccine can protect the population including pregnant women” (Participant #2, Clinical Investigator, Burkina Faso).
“When they are not aware of the benefits or risks of the clinical trial, they are afraid, but when they are aware, it is okay. But at the same time, you have to make them aware that if the clinical trial is not done in such population, there would be no data….” (Participant #2, Investigator, Burkina Faso).
“…the problem we might have recruiting is the clinicians who are managing the women, are going to be some barrier because you need to convince them why…the safety for the fetus” (Participant #5, Investigator, Ghana).
“In Africa, to participate in a study, it depends on the culture normally. I think it will depend on the community. The barrier I can face is the community I would use. I would need to explain to the community the importance of the study.” (Participant #4, Investigator, Nigeria).